Project Summary This application responds to NHLBI Participation in Research and Research Infrastructure "Grand Opportunities" (RC2) (RFA-OD-09-004) for Large-scale DNA Sequencing and Molecular Profiling of Well-Phenotyped NHLBI Cohorts. The major goal of this proposal is to apply next-generation resequencing to identify disease-causing variants influencing a key set of pediatric and adult lung diseases, the third leading cause of death in the United States. The technology we will apply involves massively parallel resequencing of all protein coding sequences in the human genome (the "exome"). In the initial discovery stage we will work with a selected sequencing center(s) to generate a catalogue of rare and common variants from 50-300 individuals selected from each of the tails of the distribution (1400 exomes total) of the major clinical phenotype assessed for each of seven population cohorts in which a comprehensive set of clinical traits have been well-characterized. Our phenotypes include: severity of lung disease in cystic fibrosis, time to acquisition of Pseudomonas aeruginosa (Pa) in cystic fibrosis, severity of lung disease in asthma, rate of decline of lung function in chronic obstructive pulmonary disease, severity of pulmonary hypertension and severity of acute lung injury. The variant catalogues from each tail will be mined by novel bioinformatics approaches to identify high-priority disease-modifying genes and/or causal variants. This genome-wide resequencing approach presents one of the most important challenges and opportunities in modern genetics. Exome sequencing can uncover low frequency alleles not currently typed or detectable by genome-wide association studies. In a second stage, we propose each high priority candidate gene or variant will be evaluated in all individuals in each cohort using conventional methods. Discovery of the genetic variants influencing these overlapping pulmonary phenotypes will substantially expand our understanding of biology of lung diseases, and will facilitate accurate diagnosis and improved management of a group of diseases that impact the very youngest and oldest in our country. Our findings may well provide insights for novel therapeutics to prevent lung disease in the U.S. and globally. PUBLIC HEALTH RELEVANCE: Project Narrative The major goal of this project is to identify the gene variations that influence the severity of lung diseases such as asthma, chronic obstructive pulmonary disease, acute lung injury, pulmonary arterial hypertension, and cystic fibrosis. This goal will be accomplished by using a novel genome-wide approach that compares the DNA sequence of every human gene among 1400 individuals of diverse ethnic ancestry. Finding these genes will improve our understanding of the biology of these acute and chronic lung diseases, improve their management, and provide information for the development of novel therapeutics.